N-acylcyclohexylamine repellants and methods of use

ABSTRACT

WHEREIN R is hydrogen, methyl, or ethyl; R1 is hydrogen or alkyl of one through four carbon atoms; and R2 is straight chain or branched alkyl of three through eight carbon atoms. Typical is N-acetyl-cis-4-n-butylcyclohexylamine useful for repelling animals.   Repelling animals with N-acylcyclohexylamines of the formula:

[72] Inventor:

United States Patent Knowles [s41 N-ACY-LCYCLOHEXYLAMINE REPELLANTS ANDMETHODS OF USE Richard N. Knowles, Hockessin, Del.

E. I. du Pontde Ncmours and Company, Wilmington. Del.

l22| Filed: Oct. 24, I968 l 2|] Appl. No.: 770,447

m... 0.5. Application Data- [60] Divisionof Ser. No. 635,306, April 20,I967, which is [73] Assignee:

a continuation-in-part of Ser. No. 574,276, Aug. l8,

782.789 l0ll957 1 June 20, 1972 Primary Eraminer-Benjamin R. PadgettAttorney-Herbert W. Larson [s71 ABSTRACT Repelling animals withN-acylcyclohexylamines of the formula:

wherein R is hydrogen, methyl, or ethyl; R, is hydrogen or alkyl of onethrough four carbon atoms;

and R, is straight chain or branched alkyl or three through eight carbonatoms. Typical is N-acetyl-cis-4-n-butylcyclohexylaminc useful forrepelling animals.

10 Claims, No Drawings N-ACYLCYCLOHEXYLAMINE REPELLANTSAND METHODS OFUSE CROSS-REFERENCE This application is a divisional of copendingapplication Ser. No. 635,306, filed Apr. 20, 1967, which in turn is acontinuation-in-part of my application Ser. No. 574,276, filed .Aug., 18, 1966.

BACKGROUND OF THE INVENTION Application Ser. No. 532,544, filed Mar. 1,1966 relates tocompounds containing cyclohexyl ring structures; andhaving utility as animal repellants.

vl have now discovered additional compounds containing a cyclohexyl ringstructure and having utility as animal. repellants.

SUMMARY OF THE INVENTION This invention relatesto.N-acylcyclohexylamines.

More specifically, this invention refers to 4-acyl-4-higheralkyl-substituted-cyclohexylamines, compositions containing them andmethods of applying them to animals.

Potent'animal inhalation irritant effectsare achieved by applying toanimals or their habitat, compounds of the formula:v

wherein R is hydrogen, methyl, or ethyl; I

R, is hydrogen or alkyl of one throughfour carbon atoms;

and

R is straight chain or branched alkyl of three through eight carbonatoms.

Substitutions onthe cyclohexyl ring must be in the cis configuration toobtain optimum irritant effects.

Preferred because of animal irritant effects at .low rates and goodresidual effects are-N-formyl and N-acetyl-cis-4-higheralkyl-cyclohexylamines.

cyclohexylarnine have potentialuse as riot control agents-dog;

repellants, deer repellants, rodent repellants and as contaminatingagents for caves or underground tunnels. Preparation I The compounds ofthis invention can, be prepared by the followingsynthetic route:

R, R and R in the following in the formula l reactions are as definedabove Those compoundswhere R- is methyl or ethyl are prepared accordingto thefollowing'reactions where R 1 becomes R' d uring reaction lX.

I mom-@mrizru LiAIH4 I ether ReCH2- NHR x a I I O mom-@mm (m'ifo DMAC 27 R o k mom s -R,

XI R2cH2@-NHR+ 110020113 II I reflux The Friedel-Crafts reaction (I).'is run by carefully adding the acid chlorideto a stirring mixture ofaluminum-chloride andbenzene. A slight-molar excess of catalyst is used;benzene serves as both a solvent and reactant. The acid chloride isadded at-.such arate'so as to keepthe temperature of the slurry at about30-40 CkThe mixture is stirred for '1 additional hour after all of theacid chloride is added, and then water is slowly added to-decompose thecatalyst. Sufficient water is added so that. all the solids aredissolved. The phenylalkyl ketone is isolated from the benzene'solutionandis purified by distillation.

The Woltf-Kishner reduction (ll) is run in 2-( Z-ethoxyethoxy)ethanolusing-a modification of the procedure given by J. Cason, eta]. inOrganic Synthesis, Collective Vol. IV, John. Wiley and Sons, New York,1963), p. 510. Once the reactants are mixed, they are heated to refluxfor a period of 3 to, 5 hours. The reflux temperature is generally inthe l30-l4 0 C. range. Aftercompletion of the reflux period, thesolution is cooled and poured into three to four volumes of water. Thealkylbenzeneproduct is extracted with pentane and purified bydistillation.

. 3 4 I The Friedel- Crafts reaction.(ll),is run by mixing approxi- Imixture since it'makes the work-up much more diflicult. ,matelyequimolar quantities of the reactants together in hex- Those amineswhich crystallize as the hemi-sulfates or sulfates ane or nitromet haneat less than 5 C. The stirring mixture is are filtered and washed withwater. It is convenient to store slowly allowed to warm to roomtemperature, and when these amines as their salts. Those aminesaltswhich fail to hydrogen chloride evolution subsides, the mixture isrefluxed 5 crystallize are converted to the free bases bymaking thesulseveral hourspvwater is then added slowly to decomposethe furicacidsolution alkaline,and extracting the amine with catalystrA sufficientquantity of water is then added so that all dichloromethane. The amineis then purified by distillation.

of the solids are dissolved. The desired acetophenone deriva- I TheSchmidt reaction proceeds without changing the cis/trans tive isisolated from the organic phase, and purified by distilla- P 'Od U' tiO1 tion. Gas-liquid chromatography on an F & M Model 500 Gas .Theacylation (Vll) can be performed by dissolving the free Chromatographerusing a 2 feet X 36. inch O.D. stainless steel amine in an equal volumeof dirnethyl-acetarnide (DMAC) or column, containing 10 percent Carbowax20M on 60-80 mesh dimethylformamide (DMF) and adding an excess of theDiatoport T indicates that about 98 percent of the desired acidanhydride to the stirring solution. This reaction is acetophenone is thel,4 isomer and 2 percent is the 1,2 l very exothermic. The solution isstirred for lO- minutes, and isomer. The-l ,2'isomer has the'shorterretention time. then it is poured into to 100 volumeeof water. The amideThe haloform reaction (IV) is run by slowly adding a cold. separates asan oil which subsequently crystallizes. 5 C.) sodium hypochloritesolution to a stirringsolution of The acylation (VII) can be performedusing the amine the 'acetophenone derivative in methanol. This is amodificasulfate directly according to the following procedure. The tion.of the procedure used by E. E. Royals (.I. Am. Chem. aminesulfate isground intoapowder,-and added toa l'zl mix.

.Soc.,:69, 1 MI I947) forv the haloform reaction of a-ionone. ture of'DMAC and 20 percent aqueous sodium hydroxide After the sodiumhypochlorite solution is added, the mixture is solution; there should bea large excess of base. The mixture is warmed to room temperature, andleft standing overnight. stirred for 10 to I S'minutes, and'then anexcess of the desired Thereafter, the mixture is heated to reflux, andthe distillate acid anhydride is added. The mixture 'warms'to about60..to collected until the pot temperature rises to 95-97 C.; most of 25 65 C. The sulfate entirely dissolves in IQ to 20 minutes. The

the methanol is distilled. The pot is then cooled to room tem- Isolution is then poured into l0 to I00 volumes ofwater. The perature. Inthose reactions where R has a low'molecular amide is isolated by theusual proceduresgiven above; weight such as n-butylthe sodium benzoatederivative The formamides of reaction Vlll are prepared by-refluxingremains dissolved; however, when Rg becomes larger such as Y the aminewith methylformate for several hours. The excess n-'heptyl-, the sodiumbenzoate derivative precipitates as a methylformate is stripped from thereaction, and the residual soapy solid. Sulfur dioxide is bubbled intothe alkaline pot formamide is purified by recrystallization. I

concentrate until the pH drops below 3. The precipitated Theseacylations proceed without changing the cis/trans benzoic acidderivative is either filtered and washed with product ratio. I water, orextracted with methylene chloride depending on In those cases whereRismethyl, or ethyl, the formamide or whether or not the benzoic acidiseasily filterable or is of a acetamide respectively is reduced bylithium aluminum soapy nature. Some of these'benzoic acid derivativescan be hydride in refluxing ether according to reaction I X. The aminerecrystallized from acetonitrile or pentane, and some are pu- 'isisolated from the reaction after the lithium aluminum rified merely bytrituration with cold pentane. I I hydride is destroyed. These aminesarepurified by distillation.

The catalytic hydrogenation (V) is performed at 2 to 3 at- Reactions Xand X] are run. according. to the procedures mospheres of hydrogen usingplatinum oxide as catalyst and described for reactions VII and VIIIrespectively. I I

glacial acetic acid as solvent; A ParrJHydrogenation Ap- An alternativesynthesis route can be used when the ap paratus is suitable for thesereactions-This reaction produces propn'ately substituted anilinederivatives are available. This a cis/trans isomerrnixture of about 2 or3/ l .The cis and trans route is illustrated below. I designation refers'to the relationship'of the 4-alkyl substituent 5 I v i I V. I I. v andcarboxyhc acid group on the cyclohexane nng, this red x11 R2011 I NHR3H} I v lustratedbelow I I I 9 .Q I I u I; I I I i 'RzCHa-@NHR I i 55 II R o Rois,

. The Schmidt reaction (Vl)is performed by dissolving the 6 vcyclohexane carboxylic acid derivative in a mixture of I chloroformandconcentrated sulfuric acid. Sodium azide is The hydrogenation (Xll) canbe pe f d' 'f to then addedin small portions tothestir'ring mixture ata'rate mospheres'of hydrogen on a Parr Hydrogenation Apparatus 7 trans gI RzCHz' N- H sufficient to keep the reaction temperature between 35,and using platinum oxide as catalyst and glacialacetic acid as-sol- I4'5" C. The" mixture is stirred at about to f- C. until the vent.Hydrogen up-take is quite slow. I I

bubbling nearly: stops. l to 3 hours). The mixture is ,then Thecis/trans ratio of the .cyclohexylamine product is abouttransferred to aseparator'yfunnel, and the lower, gelatinous 1:]. I I I I I sulfuricacidlayer is slowly dripped onto ice. The amine Reactions XIII and XlV areperformed according to reacsulfate' precipitates as a soapy materialwhich slowly crystal tions VII and VIII discussed above. The cis/transratio for the lizes. The chloroform should be kept away from the'icewater amides from Xi] and XIII is about l:l.

The amides from reactions VII, VIII, X, XI, XIII, and XIV can be usedfor the purposes of this invention without separation of the cis andtrans isomers. However, if desired, the pure amide isomers can beseparated by chromatography over silicic acid using methylcyclohexanesaturated with acetonitrile as the eluting solvent. Isomer mixtures alsocan be separated by gas-liquid chromatography using percent Carbowax 20Mon 60-80 mesh Diatoport T. In both of these chromatography methods, thecis isomer elutes before the trans isomer. Compositions 1 Compounds ofthis invention can be administered alone, but are generally contained ina composition with an inert diluent non toxic to animals. The diluentselected depends on the route of administration.

Emulsifying agents can be used with the diluent and compound of formula(I) to aid in dispersion of the active ingredient. Emulsifying agentsthat could be used include alkylaryl polyethoxy alcohols, alkyl andalkylaryl polyether alcohols, polyoxyethylene sorbitol or sorbitan fattyesters, polyethylene glycol fatty esters, fatty alkylol amidecondensates, amine salts of fatty alcohol sulfates plus long chainalcohols and oil soluble petroleum sulfonates.

. The amount of emulsifying agent in the composition will range from 0.1to 20 percent by weight.

Since the compounds of the present invention would generally beadministered by vapor or spray application, the compositions willcontain a liquid diluent such as water, acetone, hexane, gasoline,kerosene, other hydrocarbon oils, alcohols or other liquids generallyused in phannaceutical preparations.

The amount of active ingredient in the composition will vary from 0.005percent by weight to 95 percent or even higher. However, the diluentwill generally constitute the major proportion of the composition andthe amount of active ingredient will be less than 50 percent by weight.The exact concentration of the active ingredient will depend on themechanism used for administration and will be easily understood by oneknowledgeable in pharmaceutical application rates.

Application A quantity of active ingredient sufficient to causeirritation to animal tissueis l to 4,000 micrograms per liter of air atexposure of 1 minute. A rate of 5 to 4,000 micrograms per liter of airat exposure of l minute is preferred. Rates of over 4,500 micrograms perliter of air at exposure of 5 minutes kills 50 percent of the mice whichare treated.

The following additional examples are provided to more clearlyillustrate the invention.

EXAMPLE 1 A 23.9 gram quantity of 4-n-butylanilinc (from AldrichChemical Company) is dissolved in 250 milliliters of glacial aceticacid, and 1 gram of Adams Catalyst (PtO is added. The mixture is thenhydrogenated at two to three atmospheres using a Parr HydrogenationApparatus. To insure complete reduction, the hydrogenation is run overnight. The catalyst is then filtered, and the acetic acid is removedunder reduced pressure on a steam bath. The concentrate is taken up inether and washed with dilute, aqueous sodium bicarbonate. The etherealsolution is dried (MgSO filtered and evaporated in vacuum leaving 21grams of the 4-n-butylcyclohexylamine (n 1.4574). The amine is taken upin two volumes of dimethylacetamide and treated with one volume ofacetic anhydride. The temperature of the stirring solution rises rapidlyto 60-80 C. After having stirred for 10 minutes, thesolution is pouredinto 10 volumes of water. The oil which separates is extracted withether. The ethereal solution is dried (MgSO filtered and strippedleaving an oil which slowly crystallizes. This waxy solid softens at 57C. and melts from 79l00 C. Gas-liquid chromatography of this cis/transmixture of N- acetyl-4-n-butylcyclohexylamine on an F & M Model 500 GasChromatograph over 10 percent Carbowax 20M on 60-80 mesh Diatoport T ina V4 inch X 2 feet stainless steel column at a temperature of 200 C., ablock temperature of 308 C., and an injection port temperature of 280 C.with a He flow rate of 60 cc./min. shows that the cis:trans ratio isabout 1:1.

The retention times for the cis: and trans isomers are 28.0 and 32.5minutes respectively. The cis isomer causes severe burning of theoperators nose as it elutes from the column while the trans isomer doesnot cause much irritation.

The infra-red spectrum (nujol) for this mixture shows characteristicpeaks at 3,300 cm for the N-H, 1,630 and 1,560 cm for the amidecarbonyl, 1,320 cm" for thetrans isomer and 1,280 cm for the cis isomer.

Anal. Calcd. for C H NO:

C, 73.0; H, 11.8; N, 7.1%

Found: C, 72.9; H, 11.7; N, 6.7%

Mice are treated by aerosol exposure to the cis/trans mixture ofN-acetyl-4-n-butylcyclohexylamine in the following manner: The compoundis administered as an aerosol into a 2.8 liter chamber. The exposurechamber consists of a 2.8 liter bell jar over a nebullizer insertedthrough the floor of the chamber. Mice are exposed for 5 minutes to200.0 micrograms per liter (1,000Ct). The-compound is dissolved in 1.4ml. of acetone and during a span of 20 seconds the compound is sprayedup into the chamber. No further air is transferred into or out of thechamber during the 5-minute exposure.

After this exposure, irritant effects are observed in all mice exposed.The mice used as controls exposed to 1.4 m1. of acetone alone exhibit noirritant effects. Irritant effects can be described as the presence ofone or more of the following. reactive signs: I

a. hyperemia of the ears, nose and tail b. abnormal gait, includingrubbing of the nose on the floor while running about c. blinking d.salivation e. depression f. dyspnea g. hunched posture h. face-pawing.

EXAMPLE 2 In those instances where the desired amine is not reported inthe literature, the following synthesis procedure can be used. Thesynthesis of 4-n-heptylaniline will be used for the purpose ofillustration.

N-acetyl-4-n-heptanoylaniline is prepared from acetanilide andn-heptanoyl chloride in carbon disulfide with aluminum chloride ascatalyst, according to the procedure of F. Kunckell, Chem. Ber., 33,2641 (1900).

The N-acetyl-4-n-heptanoylaniline (24.7 grams; 0.1 mole) and 20milliliters of 99 percent hydrazine hydrate are added to a solution of40 grams of potassium hydroxide in 150 milliliters ofdiethyleneglycolmonoethylether. This procedure is similar to that givenby J. Cason et al., in Organic Syntheses, Collective Volume IV, p. 510.The reactants are heated for 1 hour at l30 C. The distillate iscollected until the temperature reaches 200-210 C. The reactants areheated for an additional 2 hours, and the solution is then poured into500 milliliters of ice water. The 4-n-heptylaniline is extracted fromalkaline solution and purified by distillation. This aniline derivativecan then be reduced and acylated according to the procedure in Example1.

The following aniline derivatives also can be prepared according to thisprocedure using like amounts by weight of the following materials forthe N-acetyl-4-n-heptanoylaniline used above.

Starting Material Produced 4-n-hexylaniline 4-iso-butylaniline I 4-('3-methylpentyl aniline EXAMPLES 3-l4 The following compounds can heprepared according to the procedures used in Examples l and 2 and aresubstituted one at a time in like amount by weight for theN-acetyl-4-n-butylcyclohexylamine used in Example 1. Like results areobtained.

Cis/transmixtures need not be separated; the active com- EXAMPLE 14 Dogsare exposed to vapors from a 2/1 cis/trans mixture ofN-acetyl-4-n-butylcyclohexylamine in acetone spotted on a 6 cm. circleof filter paper. The dog's head is held by an operator, and the driedpaper is held 6 to 12 cm. from the muzzle. Within 10-30 seconds, the dogsalivates, licks his lips, and occasionally face-paws. Generally, hestruggles to escape further irritant effects. As little as 2 milligramson paper can generate enough vapor at room temperature to cause visiblediscomfort in most dogs.

EXAMPLE 15 A test chamber, comprising a plastic rectangular box of 65liters, is filled with an aerosol sprayof a 2/1 cis/trans mixture ofN-acetyl-4-n-butylcyclohexylamine. The spray is administered 2 cm. abovean immobilized rabbit, and 3 cm. distant from the end of the nose. Theaerosol is aimed directly at the rabbit. Administration of compoundtakes approximately one minute. At 5,000 CT minutes), the rabbitexhibited lacrimation, nasal exudate, face pawing, and constant headshaking. After several minutes, the eyes became static after periods ofblinking. Dyspnea continued for 2 hours after exposure.

The cis isomer of Examples 14 and 15 is separated from the cis/transmixture by chromatography over silicic acid using chloroform as eluant.The weight ratio of silicic acid to cis/trans compound is 501l.

EXAMPLE l6 A 2 percent solution of N-acetyl-4-n-hexylcycIohexyI-amine indichloromethane is dispersed into and through a chamber containing thetest animals described below. This aerosol is generated by feeding thesolution of test compound through a commercial paint sprayer jet at arate of IO ml./minute and dispersing the spray with a stream of airhaving a flow rate of 44 liters/minute supplied at a pressure of 62 psi.The efficiency of forming respirable particlesranges from to 40 percent.This aerosol gives a chamber concentration of 2.l ml./liter; theparticles have a mass median diameter of 1.6 microns with a standardgeometric deviation of 2.0 microns.

After having been exposed to this aerosol for 1 minute young, adult,male guinea pigs weighing from 250-300 grams display salivation for 1hour and in some instances prostration for 20 to 60 minutes.

After rats weighing about 200 grams are exposed to this aerosol for lminute, lacrimution is observed which lasts for about 30 minutes. 7

After gerbils are exposed to this aerosol for l minute, shovelnosing isobserved which lasts for about 30 minutes. Shovelnosing is a type ofbehavior exhibited by the animal in which the animal runs around thecage rubbing the side of its face against the floor with a wipingmotion.

lclaim:

1. Method of repelling animals comprising applying to an area to beprotected from animals in an amount sufficient to cause irritation toanimal tissue, a compound of the formula:

i i -N-CR1 H Iii-(:3 H

wherein R is selected from the group consisting of hydrogen and alkyl ofone through two carbon atoms; R is selected from the group consisting ofhydrogen and alkyl of one through four carbon atoms;

R is alkyl of three through eight carbon atoms.

2. Method of repelling animals according to claim 1 wherein R ishydrogen and the compound applied.

3. Method of repelling animals according to claim 1 wherein R is methylin the compound applied.

4. Method of repelling animals according to claim 1 wherein R ishydrogen in the compound applied. 1 v

5. Method of repelling animals according to claim 1 wherein R is propylin the compound applied.

6. Method of repelling animals according to claim 1 wherein R is pentylin the compound applied.

7. Method of repelling animals comprising applying to an area to beprotected from animals in an amount sufficient to cause irritation toanimal tissue, N-formyl-cis-4-n-hexylcyclohexylamine.

8. Method of repelling animals comprising applying to an area to beprotected from animals in an amount sufficient to cause irritation toanimal tissue, N-acetyl-cis-4-n-hexylcyclohexylamine.

9. Method of repelling animals comprising applying to an area to beprotected from animals in an amount sufficient to cause irritation toanimal tissue, N-acetyl-cis-4-n-butylcyclohexylamine.

10. An animal irritant composition comprising a major amount'of an inertdiluent non-toxic to animals and an amount sufficient to causeirritation to animal tissue of a compound of the formula:

wherein R is selected from the group consisting of hydrogen and alkyl ofone through two carbon atoms; I R is selected from the group consistingof hydrogen and alkyl of one through four carbon atoms; R is alkyl ofthree through eight carbon atoms.

i i i

2. Method of repelling animals according to claim 1 wherein R ishydrogen and the compound applied.
 3. Method of repelling animalsaccording to claim 1 wherein R is methyl in the compound applied. 4.Method of repelling animals according to claim 1 wherein R1 is hydrogenin the compound applied.
 5. Method of repelling animals according toclaim 1 wherein R2 is propyl in the compound applied.
 6. Method ofrepelling animals according to claim 1 wherein R2 is pentyl in thecompound applied.
 7. Method of repelling animals comprising applying toan area to be protected from animals in an amount sufficient to causeirritation to animal tissue, N-formyl-cis-4-n-hexylcyclohexylamine. 8.Method of repelling animals comprising applying to an area to beprotected from animals in an amount sufficient to cause irritation toanimal tissue, N-acetyl-cis-4-n-hexylcyclohexylamine.
 9. Method ofrepelling animals comprising applying to an area to be protected fromanimals in an amount sufficient to cause irritation to animal tissue,N-acetyl-cis-4-n-butylcyclohexylamine.
 10. An animal irritantcomposition comprising a major amount of an inert diluent non-toxic toanimals and an amount sufficient to cause irritation to animal tissue ofa compound of the formula: